Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV.
• PDE phosphodiesterase
• Compounds disclosed herein can be useful in the treatment of CNS disorders, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans.
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• psoriasis psoriasis
• allergic rhinitis shock
• atopic dermatitis Crohn's disease
• ARDS adult respiratory distress syndrome
• eosinophilic granuloma allergic conjunctivitis
• osteoarthritis ulcerative colitis and other inflammatory diseases especially in humans.
• cyclic adenosine-3′,5′-monophosphate exhibits an important role of acting as an intracellular secondary messenger (Sutherland, Pharmacol. Rev , (1960), 12, 265). Its intracellular hydrolysis to adenosine 5′-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis.
• ARDS adult respiratory distress syndrome
• PDE cyclic nucleotide phosphodiesterases
• PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP.
• Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers.
• Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
• WO 03/47520 discloses substituted amino methyl factor Xa inhibitors.
• U.S. Patent Publication No. 2003176421, and EP 1040829 disclose prokinetic agents for treating gastric hypomotility and related disorders.
• WO 02/50070 discloses piperidine derivatives as subtype-selective N-methyl-D-aspartate antagonists.
• EP 1251128 discloses cyclohexylamine derivatives as subtype-selective N-methyl-D-aspartate antagonists.
• WO 00/59902 discloses aryl sulfonyls as factor Xa inhibitors.
• WO 01/19798 and WO01/19788 disclose novel compounds as factor Xa inhibitors.
• WO 99/23076 discloses indazole bioisostere replacement of catechol in therapeutically active compounds.
• WO 97/49702 and WO 98/09961 disclose indazole derivatives and their use as inhibitor of phosphodiesterase type IV and production of tumor necrosis factor (TNF).
• WO 97/48697 discloses substituted azabicyclo compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase.
• WO 99/57951, U.S. Pat. No. 6,339,099 discloses guanidine mimics as factor Xa inhibitor.
• the present invention provides isoxazoline derivatives, which can be used for the treatment of, but not limited to, CNS disorders, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases, and the processes for the synthesis of these compounds.
• CNS disorders CNS disorders
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• psoriasis psoriasis
• allergic rhinitis shock
• atopic dermatitis Crohn's disease
• ARDS adult respiratory distress syndrome
• eosinophilic granuloma allergic conjunctivitis
• osteoarthritis osteo
• compositions containing the compounds can be used for the treatment of CNS disorders, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
• CNS disorders AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
• COPD chronic obstructive pulmonary disease
• R 1 and R 2 can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or —OH;
• R 3 can be alkyl, alkenyl, alkynyl, cycloalkyl, carboxy, heteroaryl, heterocyclyl, aryl, heteroarylalkyl, heterocyclylalkyl, aralkyl or carboxyalkyl; and
• R 4 is cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, —CONHNH 2 , —C( ⁇ NOH)NH 2 or carboxyalkyl
• a method for treatment or prophylaxis of an animal or a human suffering from inflammatory diseases comprising administering to a patient in need thereof, an effective amount of a phosphodiesterase type IV inhibitors as described above.
• CNS disorders AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
• COPD chronic obstructive pulmonary disease
• psoriasis
• compositions for the possible treatment of diabetes and diabetes-associated complications are provided.
• the compounds can be administered orally or parenterally.
• alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, n-hexyl, n-decyl, tetradecyl, and the like exemplify this term.
• R 5 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl
• R 5 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl
• R 5 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl
• R x and R y are independently selected from R 5 or R x and R y may together join to form cycloalkyl, heteroaryl or
• substituents may be further substituted by 1-3 substituents chosen from alkyl, —COOR 5 , —NHR x , —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , —OC( ⁇ O)NR x R y , hydroxy, alkoxy, halogen, CF 3 , cyano and —S(O) m R 6 .
• Alkyl group as defined above may also be interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and —NR a — (where R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, —COOR 5 , —SO 2 R 6 , —C( ⁇ O)NR x R y ).
• alkenyl unless and otherwise specified refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, —COOR 5 , hydroxy, alkoxy, halogen, —CF 3 , cyano, —NHR x , —NH 2 , —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , —OC( ⁇ O))NR x R y and —S(O) m R 6 .
• alkynyl unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms.
• alkynyl In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, azido, cyano, halogen, hydroxy, thiol, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, —COOR 5 (wherein R 5 is the same as defined earlier), —NHR x , —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , —OC( ⁇ O)NR x R y (wherein R x and R
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, —COOR 5 , hydroxy, alkoxy, halogen, —CF 3 , —NHR x , —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , —C( ⁇ O)NR x R y , cyano and —S(O) m R 6 .
• cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a monocyclic ring or polycyclic (fused, spiro or bridged) rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained.
• Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or polycyclic ring structures such as, tricyclo[3.3.1.1]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicylco[4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo[2.2.1]heptane and the like, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, hydroxy, alkoxy, halogen, CF 3 , —NHR x —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , —OC( ⁇ O)NR x R y , cyano and —S(O) m R 6 .
• aralkyl refers to aryl linked through alkyl portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is the same as defined below.
• the examples of aralkyl groups are benzyl and the like.
• aryl herein refers to a carbocyclic aromatic group for example, phenyl, naphthyl or anthryl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen (F, Cl, Br, I), hydroxy, —COOR 5 (wherein R 5 is the same as defined earlier), alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclyloxy, heteroaryloxy, cycloalkyloxy, acyl, thioacyl, aryloxy, cyano, nitro, —NR x R y , —C( ⁇ O)NR x R y , —NHR x , —NH 2 , —(SO) m R 6 (wherein R 6 , R x , R y and m are the same as defined earlier), aryl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroaryl
• aryl group may optionally be fused with cycloalkyl group, heteroaryl group or heterocyclyl group.
• aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
• heteroaryl unless and otherwise specified refers to an aromatic monocyclic or polycyclic (fused, spiro or bridged) ring system containing 1-8 heteroatom(s) independently selected from the group consisting of N, O and S.
• the said heteroaryl ring is optionally substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, aryloxy, cycloalkyloxy, acyl, thioacyl, —COOR 5 (wherein R 5 is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, nitro, —NHR x , —NH 2 , —NR x R y , —C( ⁇ O)NR x R y , S(O) m R 6 , —OC( ⁇ O)NR x R y (wherein m, R 6 , R x and R y are the same as defined earlier).
• the substituents are attached to the ring atom, be it carbon or heteroatom.
• heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, carbazolyl, isobenzofuranyl, thianthrene, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, imidazolyl, tetrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinonyl, benzothiazinonyl and the like.
• heterocyclyl refers to nonaromatic monocyclic or polycyclic ring (fused, spiro or bridged) system having 1 to 8 heteroatoms selected from the group consisting of O, S and N.
• heterocycles containing sulphur the oxidized sulphur heterocycles containing SO or SO 2 are also included.
• the said heterocyclyl ring system is optionally benzofused or fused with heteroaryl and/or are optionally substituted wherein the substituents are selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, thioacyl, aryl, alkoxy, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, cyano, nitro, —COOR 5 (wherein R 5 is the same as defined earlier), —C( ⁇ O)NR x R y , S(O) m R 6 , —OC( ⁇ O)NR x R y , —NHR x , —NH 2 , —NR x R y (wherein m, R x and R y are the same as defined earlier).
• the substituents are attached to the ring atom, be it carbon or heteroatom.
• the said heterocyclyl ring may optionally contain one or more olefinic bond(s).
• heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, isoxazolinyl, thiazolinyl, thiazolidinonyl, oxazolinyl or oxazolidinonyl.
• Protecting groups is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T. W. Greene and P. G. M. Wuts, “Protective groups in organic synthesis”, 2 nd ED, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference.
• the species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
• the compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemic mixtures, enantiomers and diastereomers. Some compounds may also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present invention.
• Each stereogenic carbon may be of the R or S configuration.
• pharmaceutically acceptable salts refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
• the compounds of the present invention may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention.
• the compounds of the present invention may be prepared, for example, by processes described herein, although such processes are not the only means by which the compounds may be synthesised. Further, the various synthetic steps described herein may be performed in an alternate sequence in order to give the desired compounds.
• the compounds of Formulae V, VI, VII and IX can be prepared, for example, by following the procedure as described in Scheme I.
• a compound of Formula I (wherein hal is Br, Cl or I; R 1 and R 2 are the same as described earlier) can undergo formylation reaction to give a compound of Formula II, which on reaction with hydroxylamine hydrochloride can give a compound of Formula III, which can be reacted with a compound of Formula IV [wherein R z is alkyl or —CH 2 COOR 5 ; R q is —CN or COOR 5 (wherein R 5 is the same as defined earlier)] to give a compound of Formula V, path a: the compound of Formula V can be reacted with hydrazine hydrate (when R z is —CH 3 and R q is COOR 5 ) to give a compound of Formula VI, which can be reacted with triethyl orthoformate to give a compound of Formula VII, or Path b: the compound of Formula V can be reacted
• a compound of Formula II can be carried out with a formulating agent for example, dimethylformamide, triformamide, tris (diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformyl hydrazine in the presence of a base for example, butyl lithium in an organic solvent for example, tetrahydrofuran, dioxane or diethylether.
• a formulating agent for example, dimethylformamide, triformamide, tris (diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformyl hydrazine in the presence of a base for example, butyl lithium in an organic solvent for example, tetrahydrofuran, dioxane or diethylether.
• the reaction of a compound of Formula II with hydroxylamine hydrochloride to give a compound of Formula III can be carried out in an organic solvent for example, ethanol, methanol, propanol or isopropylalcohol in the presence of a base for example, sodium acetate, sodium carbonate, ammonium acetate or potassium carbonate.
• the compound of Formula V can be reacted with hydrazine hydrate (path a, when R z is —CH 3 and R q —CH 2 COOR 5 ) to give a compound of Formula VI.
• the compound of Formula VI can be reacted with triethyl orthoformate to give a compound of Formula IX.
• the compound of Formula V can be reacted with a compound of Formula VIII (path b) to give a compound of Formula IX.
• Particular illustrative compounds which can be prepared following Scheme I include:
• the compounds of Formula XI and XII can be prepared by, for example, procedures as depicted in Scheme II.
• a compound of Formula X (wherein R 1 and R 2 are the same as defined earlier) can be reacted with hydroxylamine hydrochloride to give a compound of Formula XI, which can be reacted with a compound of Formula R 1 COOH (wherein R 1 is aryl, cycloalkyl or heteroaryl) to give a compound of Formula XII.
• the compound of Formula X can be reacted with hydroxylamine hydrochloride to give a compound of Formula XI in an organic solvent, for example, ethanol, methanol, propanol or isopropyl alcohol, in the presence of a base, for example, potassium carbonate, sodium carbonate or lithium carbonate.
• an organic solvent for example, ethanol, methanol, propanol or isopropyl alcohol
• a base for example, potassium carbonate, sodium carbonate or lithium carbonate.
• the compound of Formula XI can be reacted with a compound of Formula R 1 COOH to give a compound of Formula XII in an organic solvent, for example, dimethylformamide, tetrahydrofuran, diethylether or dioxane, in the presence of a base, for example N-methylmorpholine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]-undec-7-ene or 1,4-diazabicyclo[2,2,2]octane, with a coupling agent, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
• an organic solvent for example, dimethylformamide, tetrahydrofuran, diethylether or dioxane
• a base for example N
• the compounds of Formula XIII, XVI and XVII can be prepared, for example, by following procedures as depicted in Scheme III.
• hydrolysis of a compound of Formula XIIIa to give a compound of Formula XIII can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane, in the presence of a base, for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.
• organic solvent for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane
• a base for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.
• reaction of a compound of Formula XIII with a compound of Formula XIV to give a compound of Formula XV can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, diethylether or dioxane, in the presence of a base for example, N-methylmorpholine, diisopropylethylamine, pyridine or triethylamine, with a condensing agent, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) or dicyclohexylcarbodiimide (DCC).
• organic solvent for example, dimethylformamide, tetrahydrofuran, diethylether or dioxane
• a base for example, N-methylmorpholine, diisopropylethylamine, pyridine or triethylamine
• a condensing agent for example 1-(3-d
• the compound of Formula XV can undergo ring cyclisation to give a compound of Formula XVI in an organic solvent, for example, ethanol, methanol, propanol or isopropylalcohol, in the presence of buffer, for example, sodium acetate or potassium acetate or ammonium formate.
• organic solvent for example, ethanol, methanol, propanol or isopropylalcohol
• buffer for example, sodium acetate or potassium acetate or ammonium formate.
• the reduction of a compound of Formula XIIIa to give a compound of Formula XVII can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane, with reducing agent, for example, sodium borohydride or sodium triacetoxyborohydride, in the presence of protic solvent, for example, methanol, ethanol or isopropyl alcohol.
• organic solvent for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane
• reducing agent for example, sodium borohydride or sodium triacetoxyborohydride
• protic solvent for example, methanol, ethanol or isopropyl alcohol.
• the compounds of Formula Ia and/or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides may be advantageously used in combination with one or more other therapeutic agents.
• other therapeutic agents which may be used in combination with compounds of Formula Ia of this invention and/or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides include corticosteroids, beta agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors and muscarinic receptor antagonists.
• the compounds described herein may be administered to an animal for treatment orally, or by a parenteral route.
• the pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable addition salt thereof.
• the dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity.
• the compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
• the compounds described herein can be produced and formulated as their racemic mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as the active metabolites.
• Pharmaceutical compositions comprising the molecules of Formula Ia or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced.
• Step b 1-Cyclopentyl-1H-indazole-6-carboxaldehyde oxime
• step a above a compound obtained from step a above (240 mg, 1.121 mmol) was added hydroxylamine hydrochloride (311.7 mg, 4.48 mmol) and sodium acetate (367 mg, 4.48 mmol) and ethanol (10 ml). The reaction mixture was stirred for 18 hours. The solvent was evaporated under reduced pressure and extracted the compound with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 260 mg.
• Step c 3-(1-Cyclopentyl-1H-indazol-6-yl)-5-methyl-4,5-dihydroisoxazole-5-carbonitrile
• Step a Synthesis of 2-chloro-N′-( ⁇ [3-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-5-methyl-4,5-dihydroisoxazol-5-yl]carbonyl ⁇ oxy)benzenecarboximidamide
• Step b 6- ⁇ 5-[3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-5-methyl-4,5-dihydroisoxazol-3-yl ⁇ -1-cyclopentyl-3-ethyl-1H-indazole (Compound No. 26)
• the standard compound, (n 7) rolipram, had activity of about 460 nM in the PDE-4 assay.
• Human whole blood was collected in vacutainer tubes containing heparin or EDTA as an anti coagulant.
• the blood was diluted (1:1) in sterile phosphate buffered saline and 10 ml. was carefully layered over 5 ml Ficoll Hypaque gradient (density 1.077 g/ml) in a 15 ml conical centrifuge tube.
• the sample was centrifuged at 3000 rpm for 25 minutes in a swing-out rotor at room temperature. After centrifugation, interface of cells were collected, diluted at least 1:5 with PBS and washed three times by centrifugation at 2500 rpm for 10 minutes at room temperature.
• the cells were resuspended in serum free RPMI 1640 medium at a concentration of 2 million cells/ml. Alternatively whole blood was used.

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